Interstitial lung disease (ILD), also known as diffuse parenchymal lung disease (DPLD), refers to a group of lung diseases affecting the interstitium (the tissue and space around the air sacs of the lungs). It concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues. Idiopathic pulmonary fibrosis (IPF) is defined as a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and associated with a histological pattern of usual interstitial pneumonia (UIP). IPF lungs are characterized by architectural destruction, dense scarring with honeycombing and scattered fibroblasts foci (areas of intensive fibroblasts proliferation). IPF has a progressive and usually fatal course with a medium survival of 2-3 years following diagnosis. Patients with IPF are usually between 50 to 70 years old and the incidence is 7.4 cases per 100,000 for women and 10.7 cases per 100,000 for men per year. The incidence, prevalence and death increase with age. To date, most treatment strategies have been based on eliminating or suppressing the inflammatory component. No pharmacological therapy has been proven to be effective in IPF treatment. All currently available therapeutic trials in IPF are severely limited by the lack of clear understanding of the disease etiology. The original hypothesis of the pathogenesis of IPF is that chronic inflammation in response to unknown etiological agents (idiopathic) leads to tissue destruction, initiation and propagation of wound healing responses and, subsequently, to progressive fibrosis. A recent proposal indicates that inflammation is necessary to trigger the initiation of the fibrotic process, but plays a minor role in the progression of the disease. In contrast to other forms of chronic interstitial lung diseases such as sarcoidosis and hypersensitivity pneumonitis, IPF is characterized by only limited inflammation.
Recently, it has been suggested that IPF is mainly a disorder of alveolar epithelial injury, abnormal alveolar wound repair and remodelling.
Transforming growth factor-β1 (TGF-β1) is a highly pleiotropic cytokine which plays a fundamental role in wound healing, embryonic development and disease states associated with inflammation and proliferation, for example tissue fibrosis. In the adult mice, TGF-β overexpression in the lungs leads to progressive pulmonary fibrosis. TGF-β is thought to promote fibrotic responses in the lungs mainly due to suppression of alveolar epithelial cell proliferation, stimulation of fibroblasts proliferation, activation of resident lung cells including epithelial cells, which differentiate into collagen-producing myofibroblasts. TGF-β1 enhances synthesis and inhibits degradation of extracellular matrix components. Moreover, recent studies suggest that TGF-β1 may contribute to fibrotic conditions by modulating procoagulant and fibrinolytic activities. In particular, TGF-β1 has been shown to upregulate the expression of tissue factor, the key initiator of the extrinsic coagulation pathway, and of the plasminogen activator inhibitor (PAI)-1 in different cell populations including fibroblasts.
The cellular response to TGF-β1 involves ligand binding to TGF-β receptor type II (TβR-II) which phosphorylates TGF-β receptor type I (TβR-I). Activated TβR-I phosphorylates receptor associated Smads (Smad 1, 2, 3, 5, and 8), promoting their heterodimerization with common-mediator Smad (Smad 4) and translocation from the cytoplasm to the nucleus. Within the nucleus, the Smad hetero-complex interacts with canonical smad-binding elements (SBEs) of target genes to activate their transcription. Human Smad 3 and Smad 4 have been shown to bind to SBE comprising CAGA box.
Alterations of the alveolar haemostatic balance and excessive deposition of intraalveolar fibrin have been observed in the lungs of IPF patients. Intraalveolar fibrin accumulation, observed under these conditions, arises from the imbalance between locally produced pro- and anti-coagulant factors, in combination with leakage of plasma proteins (including fibrinogen) into the alveolar space. Increased procoagulant activity in bronchoalveolar lavage (BAL) fluids of patients with IPF is accompanied by a decreased fibrinolytic activity. Identical alterations of the haemostatic balance in the alveolar space have been observed in the bleomycin animal model of pulmonary fibrosis. In clinical and experimental lung fibrosis the procoagulant response is mainly attributable to tissue factor (TF) associated with factor VIIa, whereas the decreased fibrinolytic activity is ascribed to inhibition of urokinase type (u-PA) and tissue type (t-PA) plasminogen activators by plasminogen activator inhibitor (PAI)-1 as well as blockage of plasmin by α2-plasmin inhibitor. Although fibrin is required for reparative processes and normal wound healing, persistent and excessive deposition of extravascular fibrin is thought to contribute to the pathomechanisms of fibrotic lung diseases in several ways. Fibrin may serve as a reservoir of profibrotic growth factors. It incorporates and inactivates pulmonary surfactant, the lung lipoprotein complex critical for maintaining low alveolar surface tension. Surfactant dysfunction leads to atelectasis and loss of lung compliance. Moreover, inactivation of the surfactant system, in conjunction with “glueing” of the adjacent alveolar walls by fibrin, is thought to provide a provisional matrix on which fibroblasts proliferate and produce collagen.
In addition, the u-PA/PAI-1 system may contribute to development of lung fibrosis by regulation of cell migration, cell adhesion and cell proliferation. Furthermore, various coagulation proteases such as thrombin, factor Xa and the TF/factor-VIIa complex exhibit cellular activities that may also contribute to fibrotic processes in the lung. Most of these functions are mediated via proteolytic activation of protease activated receptors (PARs). For instance, thrombin and factor Xa stimulate fibroblast proliferation and procollagen production in a PAR-1-dependent manner. Additionally, thrombin induces differentiation of normal lung fibroblasts to myofibroblasts via PAR-1 activation. Furthermore, activation of PAR-1 by thrombin, factor Xa and by the TF/factor VIIa complex can increase the expression of profibrotic and proinflammatory cytokines. A potential role of PAR-1 in pulmonary fibrosis is underscored by the recent finding demonstrating that PAR-1-deficient mice are protected against bleomycin-induced lung fibrosis. Additional evidence underlying the importance of cellular effects mediated by haemostatic factors in the development of lung fibrosis came from the recent observation indicating no protection against bleomycin-induced lung fibrosis in fibrinogen-null mice.